An updated systematic review and meta-analysis of efficacy and safety of Chinese herbal medicine for treating atopic dermatitis

Abstract

Background

This systematic review evaluated the Chinese herbal medicine (CHM) for treating atopic dermatitis (AD).

Methods

PubMed, EMBASE, the Cochrane library, the Wanfang database, and China National Knowledge Infrastructure (CNKI) were searched for relevant randomized controlled trials (RCTs) from inception to December 2021. Overall recovery rate, disease/symptom severity scoring, quality of life (QoL), recurrence rate, and incidence of adverse events (AEs) were evaluated. STATA SE 14.0 software was used for statistical analysis.

Results

17 RCTs involving 1624 patients were eligible. CHM was associated with a higher overall recovery rate (risk ratio [RR] = 1.15, 95% confidence interval [CI]: 1.05, 1.26, p = .003) and decreased recurrence rate (odds ratio [OR] = 0.19, 95% CI: 0.07, 0.55, p = .002), both confirmed by sensitivity analyses. CHM could decrease scoring atopic dermatitis index (MD = −0.61, 95% CI: −1.12, −0.11, p = .017), however, sensitivity analysis revealed non-robustness. No significant differences were found between the CHM and the control group in Eczema Area and Severity Index, QoL, and the incidence of AEs.

Conclusions

CHM was effective for treating AD as it could improve the overall recovery rate and decrease the recurrence rate. More studies are required to validate the potential of CHM on disease/symptoms severity and QoL.

Keywords:

• Atopic dermatitis
• atopic eczema
• Chinese herbal medicine
• meta-analysis

Introduction

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by severe itchiness, skin redness and dryness, weeping, scarring, and lichenification (1). Data from the previous study indicated that AD affects approximately 15% to 30% of children and 2% to 10% of adults (2). More importantly, AD significantly affects daily living activities and leads to an increased financial burden for patients and their caregivers (3). Therefore, establishing effective treatment for AD is of utmost importance.

At present, conventional treatments for AD continue to hold sway, such as topical therapies(topical corticosteroids, calcineurin inhibitors and antibiotics/antimicrobials), as well as systemic therapies(phototherapy, systemic corticosteroids, cyclosporine and methotrexate, etc) (4). The former is mostly used for the first-line treatment of mild or severe AD patients while the latter is the main choice for severe and intractable ADs. In recent years, with the in-depth study of the pathological mechanism of AD, the use of small molecule targeted drugs and biologics has been widely concerned. JAK inhibitors (upadacitinib and abrocitinib), as representatives of small molecule targeted drugs, can improve the skin lesions and relieve itching in AD patients by blocking the common intracellular conduction pathways of various cytokines (5). In addition, a large number of studies confirmed that the signal transduction mediated by interleukin (IL)-4 and IL-13 participated in the type 2 inflammatory reaction in the pathogenesis of AD, and IL-31, as a cytokine mainly produced by activated T cells, was also confirmed to be closely related to the pruritus of AD (6). Based on the above researches, The United States Food and Drug Administration (FDA), the European Commission and the Japanese Dermatology Association (JDA) (6) approved IL-4Rα inhibitor (Dupilumab), IL-13 inhibitor (tralokinumab) and IL-31Rα inhibitor (nemolizumab) respectively, in order to cope with AD patients with no obvious improvement after a period of common therapy, or the remaining intractable AD-related pruritus after a period of common therapy. Although the above therapies occupy the mainstream and are recognized by several national guidelines, the incidence of adverse events that cannot be ignored and the progress of drug resistance have always been a major concern for patients and health care professionals, such as glucocorticoid (4). Therefore, it is of great significance to find drugs that are more effective, have fewer side effects or are suitable for a wider range of people.

As we all know, the application and treatment of traditional Chinese medicine in AD has been paid more and more attention internationally. The pathological formation of AD is multifactorial. Compared with modern medical preparations with a single component, oral or topical Chinese herbal medicine with multiple components may play a therapeutic role through multiple targets. For example, Hon found that the external washing formula of traditional Chinese medicine (honeysuckle, Polygonatum, licorice, etc.) had good antibacterial activity, especially for Staphylococcus aureus (7). Ahn et al. showed that topical application of Jaungo ointment, which consists of Zicao (Radix arnebiae) and Danggui (Angelicae radix), could ameliorate the chronic-phase symptoms of AD (8). Lee et al. reported that SSHT (a traditional Chinese medicine prescription, including Glycyrrhiza uralensis Fisch, Pinellia ternata, Bupleurum chinense DC, Bupleurum chinense DC, Ginseng DC, etc.) can relieve AD symptoms by regulating inflammatory mediators (9). Two previously published systematic reviews on CHM for AD were inconclusive due to the poor quality of included studies and substantial statistical heterogeneity in selecting outcome measures (10,11). Therefore, it is necessary to comprehensively and systematically summarize and analyze the existing high-quality randomized controlled trials. This systematic review with meta-analysis aimed to further evaluate the therapeutic efficacy and safety of CHM for treating AD by comprehensively evaluating high-quality RCTs.

Material and methods

The present systematic review with meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guideline (12).

Search strategy

PubMed, EMBASE, the Cochrane library, the Wanfang database, and China National Knowledge Infrastructure (CNKI) were comprehensively searched for relevant studies from their inception until December 2021. We used the medical subject heading (MeSH) term of ‘Dermatitis, Atopic,’ ‘Medicine, Chinese Traditional,’ ‘Medicine, East Asian Traditional,’ ‘Herbal Medicine,’ ‘Drugs, Chinese Herbal,’ ‘Plants, Medicinal,’ and ‘Herbal Therapy’ as well as relevant keywords to develop the search strategy. The detailed search strategy of targeted English databases is summarized in Table S1.

Eligibility criteria

Inclusion criteria were as follows: (1) patients diagnosed with atopic dermatitis, or children/infants diagnosed with ‘eczema’; (2) intervention and control: Chinese herbal medicine + modern medicine vs. modern medicine alone; Chinese herbal medicine vs. placebo; (3) studies that reported at least one of the following outcomes: overall recovery rate (evaluated as cure and improvement rate), disease/symptom severity (evaluated by Eczema Area and Severity Index [EASI] or scoring atopic dermatitis index [SCORAD]); quality of life (QoL, evaluated by Dermatology Life Quality [DLQI]), recurrent rate, and the incidence of adverse events (AEs) at the last follow-up; 4) study design was limited to randomized controlled trial (RCT); 5) language was restricted to English or Chinese.

Exclusion criteria were the following: (1) repeated reports of the same study; (2) single-arm studies, case reports, case series, and reviews; and (3) studies with incomplete data.

Data extraction

Eligible studies were selected by two independent reviewers through two stages, which included screening titles and abstracts and checking full texts. Disagreements regarding study selection were resolved by consulting a third reviewer. The following data were extracted from each eligible study: author’s name, publication year, study design, country, sample size, mean age, diagnostic criteria, detailed interventions, dose, disease duration, follow-up duration, and outcomes.

Risk of bias assessment

We assessed the risk of bias in the included studies by using the seven items from the Cochrane risk of bias assessment tool (RoB) (13), including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias resources. The overall quality of each study was rated as ‘low’, ‘unclear’, or ‘high’ risk according to the assessment results.

Statistical analysis

The risk ratio (RR) with a 95% confidence interval (CI) was used to express the pooled results of dichotomous variables, including overall recovery rate, recurrence rate, and incidence of AEs. We used mean difference (MD) with a 95% CI to express the pooled results for continuous variables, including EASI, SCORAD, and QoL. We used Cochrane Q and I² statistics to evaluate statistical heterogeneity across studies. When p < .10 and I²≥50%, statistically significant heterogeneity is considered to exist between studies and a random effects model would be used for meta-analysis. In contrast, the statistical heterogeneity across studies is insignificant if p ≥ .1 and I²<50%, then the fixed-effects model would be adopted for meta-analysis. We conducted a sensitivity analysis by introducing the leave-one-out method to examine the robustness of the pooled results. We also performed subgroup analysis regarding disease/symptoms severity according to the different measurements. In addition, more than ten studies reported an overall recovery rate as an outcome, allowing publication bias to be assessed by Egger’s and Begg’s tests. In all cases, p < .05 were considered statistically significant. STATA SE 14.0 software (Stata Corp, College Station, Texas, USA) was used to perform all statistical analyses.

Results

Identification of eligible studies

Initially, we identified 33 records from PubMed, 21 from EMBASE, 51 from the Cochrane library, 387 from Wanfang, and 58 from CNKI. Moreover, additional three studies were identified after checking the previous meta-analyses and the reference lists of included studies. After the initial removal of 157 duplicate records, 337 ineligible studies were excluded after screening titles and abstracts. After screening the full texts of 50 studies, 33 ineligible ones were excluded for the following reasons: non-RCTs (n = 7), lack of outcomes of interest (n = 14), and ineligible interventions (n = 7). Finally, 17 studies (8,9,14–28) were included in this meta-analysis. The identification and selection of eligible studies are illustrated in Figure 1.

Figure 1. The process of retrieval and selection of eligible studies. CNKI: China National Knowledge Infrastructure.

Study characteristics

Among the 17 RCTs, 1624 patients with AD, atopic eczema (AE), or infantile eczema were finally included. The study characteristics are shown in Table 1. The mean age of the patients assigned to receive CHM ranged from 8.01 months to 38.6 years, compared to 7.65 months–39.6 years in those patients in the control group. The proportion of males varied from 16.7% to 68.6% in the CHM group and 11.2%–90.9% in the control group. The disease duration of patients in the CHM group ranged from 9 days to 17.5 years, and that in the control group ranged from 8 days to 18.2 years. Follow-up duration ranged from 2 to 24 weeks. Detailed baseline characteristics of each eligible study are summarized in Table 1.

Table 1. Baseline characteristics of 17 included studies.

Study ID	Country	Simple size I/C	Diagnosis	Regimen I/C	Detailed ingredients of CHM protocol	Age (mean or range) I/C	Gender, male, n (%)	Disease duration I/C	Follow-up (week)	Outcomes
Kobayashi et al. (18)	Japan	37/40	AD	Hochu-ekki-to (Chinese name: Bu-Zhong-Yi-Qi Tang); 7.5 g/day	Astragali radix (16.7%), Atractylodis lanceae rhizoma (16.7%), Ginseng radix (16.7%), Angelicase radix (12.5%), Bupleuri radix (8.3%), Zizyphi fructus (8.3%), Aurantii nobilis pericarpium (8.3%), Glycyrrhizae radix (6.3%), Cimicifugae rhizoma (4.2%) and Zingiberis rhizoma (2.0%)	NR	20–40	NR	24	ORR
Lin et al. (21)	China	32/16	AD	Qingdai (indigo naturalis power) ointment/Placebo; 2/d, 6w	2.80% indigo blue and 0.15% indirubin, without clearly reported doses.	21.9/23Y	20(63)/9(56)	17.5/18.2Y	6	EASI, DLQI, AEs
Ahn et al. (8)	Korea	11/12	AD	Jaungo (Chinese name: Shiunko)/placebo; 2/d, 3w	Angelica sinensis and Lithospermi radix, without clearly reported doses.	20.82/21.67Y	3(27.3)/4(33.3)	11.70/14.67Y	NR	EASI, SCORAD
Yen and Hsieh (27)	China	15/16	AD	Tzu-Yun ointment/betamethasone valerate cream; 2/d, 8w	Arnebia euchroma 120 mg, cera flava 300 mg, A. Sinensis 60 mg, and sesame oil (quantum sufficit)	32.9/39.6Y	10(66.7)/10(62.5)	96.3/73.6D	8	EASI
Chen et al. (14)	China	55/55	AE	CMM fumigant and desonide cream/desonide cream; 30 min*2/d, 7d	Sophora flavescents 60 g, Fructus Cnidii 30 g, Fructus Scopariae, Cortex Phellodendri 15 g, Radix Angelicae Dahuricae 15 g, Rhizome Acorus Tatarinowii 10 g	5.35/5.26Y	30(54.5)/28(50.9)	2.41/2.04Y	6	ORR, EASI, Recurrence rate
Han et al. (16)	China	23/22	AD	Chinese medicine bath and Trarolimus/Trarolimus; 1/d, 4w	Cortex Phellodendri 30 g, Angelica sinensis 15 g, S. Miltiorrhiza 30 g, Poria cocos 30 g, Atractylodes macrocephala 30 g, Portulaca oleracea 30 g, Caulis spatholobi 30 g, Dictamni Cortex 15 g	9.61/10Y	13(56.5)/12(54.5)	NR	3	ORR, SCORAD, Recurrence rate
He (17)	China	84/87	Eczema	Chinese medicine Wuhuang liquid/free; 15 min*3/d, 10d	Radix Scutellariae 15 g, Radix Astragali 15 g, Rhizoma Coptidis 30 g, Cortex Phellodendri 30 g,and Rheum Officinale 15 g	16D–9M/17D–8M	47(56.0)/49(56.3	9.0/8.0D	NR	ORR
Juan and Zhi-Xiong (19)	China	40/40	Eczema	Chinese medicine and vitamin E allantoin cream/ desonide cream; 10 min*2/d, 7d	Angelica Sinensis 20 g, Fructus Kochiae 20 g, Cortex Dictamni 20 g, Fructus Cnidii 20 g, Rodix Sophorae Flavescentls 20 g, Herba Andrographitis 20 g and Feverfew 20 g	8.01/7.65M	25(63.0)/22(55)	3.15/3.01M	NR	ORR, EASI, AEs, recurrence rate
Li et al. (20)	China	35/35	AD	Chinese medicine bath and tacrolimus/tacrolimus; 10–20 min*1/d, 4w	Cortex Phellodendri 20 g, Angelica sinensis 15 g, S. Miltiorrhiza 15 g, Poria cocos 15 g, Atractylodes macrocephala 20 g, Portulaca oleracea 20 g, Caulis spatholobi 20 g, Dictamni Cortex 20 g	6.4/6.6Y	20(50)/22(55)	1.4/1.6Y	NR	ORR, SCORAD, AEs
Mai (23)	China	39/39	Eczema	Chinese medicine washing/homemade Chinese medicine ointment; 1/d, 7d	Fructus Cnidii, Rodix Sophorae Flavescentls, Fructus Kochiae, Calcined Alum and Cortex Dictamni Radicis	9.0/8.5M	23(59.0)/22(56.4)	NR	NR	ORR, AEs
Tao (24)	China	43/42	Eczema	Chinese medicine and hydrocortisone butyrate cream/hydrocortisone butyrate cream; 20 min*3–4/d, 7d	Herba Schizonepetae 20 g, Radix Saposhnikoviae 20 g, Radix Angelicae Dahuricae 20 g, Forsythia suspensa 20 g, Lonicera japonica 20 g, Radix Sophorae Flavescentis 20 g, Fructus Kochiae 20 g and Fructus Cnidii 20 g	7D–12M	15(34.9)/12(28.6)	NR	NR	ORR, recurrence rate
Dongsheng et al. (25)	China	118/85	AD	Qingdai (Indigo) powder and hydrocortis, erythromy/hydrocortis, erythromy; 3/d, 1–2w	2.80% indigo blue and 0.15% indirubin, without clearly reported doses.	2–6M, 81.3%	65(55.1)/48(56.5)	1W–2M	24	ORR
Wu (26)	China	45/45	AD	Chinese medicine and Calamine polish/Calamine polish; 15 min*2/d, 7d	Angelica Sinensis 20 g, Fructus Kochiae 20 g, Cortex Dictamni 20 g, Fructus Cnidii 20 g, Rodix Sophorae Flavescentls 20 g, Herba Andrographitis 20 g and Feverfew 20 g	5.8/5.7Y	23(51.1)/24(53.3)	3.8/3.6Y	2	ORR, AEs, recurrence rate
Zhu and Chen (28)	China	140/140	AD	Chinese medicine and hydrocortisone butyrate cream/hydrocortisone butyrate cream; 20 min*1/d, 2w	Radix Saposhnikoviae 10 g, Phellodendron amurense 20 g, Lonicera japonica 20 g, Purslane 30 g, Radix Sophorae Flavescentis 30 g and Fructus Kochiae 30 g	5.44/5.59Y	96(68.6)/94(67.1)	11.41/11.87M	2	ORR, SCORAD
Lee et al. (9)	Korean	30/30	AD	Soshiho-tang (Xiao-chai-hu-tang)	Bupleurum falcatum L. 2.33 g, Pinellia ternate 1.67 g, Zingiber officinale Roscoe 1.33 g, Scutellaria baicalensis Georgi 1.00 g, Ziziphus jujuba var. inermis Rehder 1.00 g, Panax ginseng C.A.Mey. 1.00 g, Glycyrrhiza uralensis Fisch 0.67 g, lactose hydrate 1.31 g, and corn starch 0.315 g	12.17/12.47Y	15(50)/14(46.7)	NR	8	SCORAD
Gu et al. (15)	China	15/13	AE	CHM /placebo; 2/d, 12w	Atractylodes macrocephala, Pseudostellaria heterophylla, Dioscorea opposita, Coix lacryma-jobi, Imperata cylindrica, Forsythia suspensa, Glycyrrhiza glabra, Dictamnus dasycarpus and Pteria martensii, without clearly reported doses.	6–16Y	9(30)	NR	4	EASI, DLQI
Liu et al. (22)	China	72/73	AD	Combination of traditional Chinese medicine therapy	Radix Pseudostellariae 10 g, Forsythia suspensa 10 g, Ramulus Uncariae cum Uncis 10 g, Medulla Junci 3 bundles, Herba Lophatheri 10 g, Semen Coicis 10 g, Rhizoma Dioscoreae 10 g, Concha Ostreae 10 g, Radix Glycyrrhizae 3 g	13.9/13.44Y	31(43.1)/30(41.1)	9.44/8.38Y	36	SCORAD, AEs

Note: AD: atopic dermatitis; AE: atopic eczema; I/C: intervention/comparison; NR: no report; CHM: Chinese herbal medicine; CMM: Chinese materia medica; ORR: overall recovery rate; EASI: Eczema Area and Severity Index; SCORAD: Scoring Atopic Dermatitis Index; DLQI: Dermatology Life Quality Index; AEs: adverse events; DAC: Deutsche Arzneimittel-Codex; D: day; W: week; M: month; Y: year.

Risk of bias assessment

According to the Cochrane risk of bias assessment criteria, five studies were rated as low risk, nine studies were rated as moderate risk, and the remaining three were rated as high risk. Detailed results of the risk of bias assessment of all studies are summarized in Table 2.

Table 2. Detailed results of risk of bias assessment.

Study	Random sequence generation (selection bias)	Allocation concealment (selection bias)	Blinding of participants and personnel (performance bias)	Blinding of outcome assessment (detection bias)	Incomplete outcome data (attrition bias)	Selective reporting (reporting bias)	Other bias sources	Overall risk
Kobayashi et al. (18)	+	+	+	+	+	+	+	Low
Lin et al. (21)	+	+	+	+	+	+	+	Low
Ahn et al. (8)	+	+	+	+	+	+	+	Low
Yen and Hsieh (27)	+	?	?	?	+	+	+	Moderate
Chen et al. (14)	+	?	?	?	+	+	+	Moderate
Han et al. (16)	+	?	?	+	+	+	+	Moderate
He (17)	−	−	?	?	+	+	+	High
Juan and Zhi-Xiong (19)	+	?	?	?	+	+	+	Moderate
Li et al. (20)	+	?	?	?	+	+	+	Moderate
Mai (23)	+	?	?	?	+	+	+	Moderate
Tao (24)	?	?	?	?	+	+	+	Moderate
Dongsheng et al. (25)	+	?	?	?	+	+	+	Moderate
Wu (26)	−	?	?	?	+	+	+	High
Zhu and Chen (28)	+	−	?	?	+	+	+	Moderate
Lee et al. (9)	+	+	+	+	+	+	+	Low
Gu et al. (15)	+	+	+	+	+	+	+	Low
Liu et al. (22)	+	+	−	+	+	+	+	High

Overall recovery rate

Eleven studies (14,16–20,23–26,28) reported overall recovery based on cure and improvement rate at the last follow-up. There was significant statistical heterogeneity across studies with reference to this outcome (I²=73.8%, p < .001). Therefore, we selected the random-effects model for meta-analysis, and the pooled result showed that CHMs were associated with a significantly improved overall recovery rate (RR = 1.28, 95%CI: 1.16, 1.41, p < .001) (Figure 2). As shown in Figure S1, sensitivity analysis further substantiated the robustness of the pooled result.

Figure 2. Meta-analysis of overall recovery rate. CI: confidence interval.

Disease/symptoms severity

Six studies (8,9,16,20,22,28) used SCORAD to evaluate the disease/symptoms severity; however, there was significant statistical heterogeneity across studies in terms of this outcome (I²=87.1%, p < .001). Therefore, we selected the random-effects model for meta-analysis, and the pooled result suggested that CHMs significantly decreased the SCORAD compared to controls (MD= −0.61, 95% CI: −1.12, −0.11, p = .017) (Figure 3(A)). However, as shown in Figure S2, the pooled result was significantly changed after removing the study by Li et al. (20).

Figure 3. Meta-analysis of disease/symptoms severity based on (A) SCORAD and (B) EASI. MD: mean difference; SCORAD: scoring atopic dermatitis index; EASI: Eczema Area and Severity Index.

Six studies (8,14,15,19,21,27) evaluated disease/symptoms severity using EASI; however, there was significant statistical heterogeneity across studies concerning this outcome (I²=87.2%, p < .001). Thus, we selected the random-effects model for meta-analysis, and the pooled result showed no significant difference between the two groups (MD = −0.55, 95% CI: −1.24, 0.13, p = .113) (Figure 3(B)). However, after removing the study by Chen et al. (14), the pooled result was significantly changed to benefit CHMs, as shown in Figure S3.

Recurrence rate

Among 17 included studies, 5 (14,16,19,24,26) evaluated the recurrence rate after treatment. There was insignificant statistical heterogeneity across studies regarding this outcome (I²=45.0%, p = .122). Therefore, we selected the fixed-effects model for meta-analysis. The pooled result suggested that patients receiving CHMs experienced fewer recurrences compared to patients receiving controls (RR = 0.26, 95% CI: 0.16, 0.42, p < .001) (Figure 4). Sensitivity analysis further substantiated the robustness of the pooled result as it did not significantly change after removing each study (Figure S4).

Figure 4. Meta-analysis of recurrence rate. CI: confidence interval.

Incidence of AEs

Six studies (19–23,26) reported the incidence of AEs. As there was insignificant statistical heterogeneity across studies regarding this outcome (I²=19.5%, p = .287), we selected the fixed-effects model for meta-analysis. The pooled result suggested no significant difference between the two groups in the incidence of AEs (RR =0.78, 95% CI: 0.55, 1.13, p = .187) (Figure 5). Sensitivity analysis further substantiated the robustness of the pooled result as it did not significantly change after removing each study (Figure S5).

Figure 5. Meta-analysis of the incidence of AEs. CI: confidence interval; AEs: adverse events.

QoL

Among 17 included studies, 2 (15,21) evaluated the QoL using DLQI; however, there was no significant statistical heterogeneity across studies regarding this outcome (I²=0.0%, p = .702). Therefore, we selected the fixed-effects model for meta-analysis. The pooled result revealed no significant difference between the two groups (MD = −0.18, 95% CI: −0.64, 0.29, p = .459), and sensitivity analysis did not significantly change the pooled result (Figure S6).

Publication bias

After conducting Egger’s and Begg’s tests, we detected that the pooled result of the overall recovery rate (Egger’s test: t = 4.10, p = .003; Begg’s test: z = 2.49, p = .013) might be affected by the publication bias; however, publication bias was absent for SCORAD (Egger’s test: t = 2.25, p = .110; Begg’s test: z = 0.38, p = .707), EASI (Egger’s test: t = 1.77, p = .151; Begg’s test: z = 1.13, p = .260), recurrence rate (Egger’s test: t = −1.02, p = .383; Begg’s test: z = 0.73, p = .462), and the incidence of AEs (Egger’s test: t = −1.57, p = .192; Begg’s test: z = 1.50, p = .133). In addition, a publication bias examination was not conducted for QoL due to insufficient studies.

Discussion

This systematic review with meta-analysis revealed that CHM, in combination with modern medicine, could improve the overall recovery rate and decrease the recurrence rate among patients with AD, AE, and eczema. However, the therapeutic potential of CHM on disease/symptoms remained uncertain. In addition, CHM did not reduce the incidence of AEs and improve QoL compared to modern medicine or placebo.

The complementary or alternative treatment strategy of traditional Chinese medicine in treating atopic rash was mainly selected by Chinese doctors, so we referred to the Consensus of experts in TCM diagnosis and treatment of eczema (29). The guide showed that the diagnosis and treatment of atopic dermatitis in traditional Chinese medicine can be roughly divided into two aspects, the internal treatment and the external treatment. The Internal treatment refers to the treatment of etiology (oral administration is mostly used), aiming at regulating physical fitness, improving overall recovery rate, reducing recurrence rate and improving quality of life. Drugs such as honeysuckle, Polygonatum sibiricum, Poria and Forsythia suspensa are frequently used in this respect and are representative drugs for internal treatments. AD is a chronic inflammatory skin disease, in which the immune balance between Th1 and Th2 is a part of the pathogenesis. Studies have found that Poria cocos protein is the main component of Poria cocos, which can activate Th1 immune response, inhibit Th2 cytokines and immunoglobulin E (30), and inhibit the occurrence of AD-like dermatitis in NC/Nga mice treated with 2,4-dinitrofluorobenzene by regulating Th1 immune response. Hao et al. (31) reported that forsythia suspensa extract significantly inhibited the proliferation of T lymphocytes and the synthesis of interleukin −4(Th2 cytokine) induced by glycine. Therefore, above traditional Chinese medicines may improve the skin lesions of AD by regulating the immune balance between Th1 and Th2. The external treatment is symptomatic treatment (the route of administration is mostly local external use), and the main purpose is to relieve symptoms. Common drugs are indigo naturalis, Lithospermum, Cortex Phellodendri, etc. Studies have shown that indigo naturalis can inhibit skin inflammation by inhibiting the production of cytokines, the activity of nuclear factor kappa B and the activation of mitogen-activated protein kinase (32). Jaungo ointment (Radix Arnebiae and Radix Angelicae Sinensis, etc.) has been produced since 2013 as a medicine for treating dry skin, frostbite, mites, anal fissure and nasal dermatitis (8). Recently, non-clinical studies have shown that Jaungo can play an anti-allergic and anti-inflammatory role in AD mouse model for two weeks (32).Although the two treatments have their own emphases, they are not antagonistic, but often used jointly to play a role together.

Tan et al. evaluated the efficacy and safety of oral CHM for 432 AD patients based on seven RCTs published between 1992 and 2010 (11). They performed qualitative analyses by comparing CHM combined with modern medicine (MM) versus MM alone and CHM versus placebo to assess disease or symptom severity scores, QoL, and reduction in concurrent treatments. Due to the poor quality of the included RCTs and statistical heterogeneity in outcome measurements, the data on overall clinical scoring, including SCORAD and EASI, pruritus score, QoL, and AEs, were not quantitatively summarized. Other efficacy indicators mentioned in our study, such as recurrence rate, were not described. They only conducted meta-analyses on erythema and surface damage scores, and the results favored CHM compared to placebo. In addition, they applied different herbal ingredients, CHM formulations, TCM theory, and delivery methods compared with our meta-analysis. Nevertheless, Tan et al. suggested that CHM significantly improves symptom severity of AD and is well tolerated, which was consistent with our findings. Moreover, our study included 17 RCTs with high quality that have been published recently, which might provide more updated and comprehensive CHM treatment information and reduce the bias in the analysis.

Gu et al. reviewed the topical application of CHM in AE patients (10) in their meta-analysis. All included studies were published between 2003 and 2012 and conducted in China. A total of 34 CHM derived from plants, insects, and mineral substances under 12 CHM theory categories were covered. Among them, Huangbai (Cortex phellodendri) was the most used herb, followed by Huanglian (Rhizoma coptidis), She-chuangzi (Fructus cnidii), Zicao (Radix arnebiae), and Bingpian (Borneolum syntheticum). Moist dressing of CHM, oil-based CHM preparation, or ointment applications on the affected skin areas were reported. There were methodological weaknesses in the included ten RCTs. All RCTs were assessed as having a high risk of performance bias regarding the blinding of personnel and participants. Total effectiveness rate, i.e., a sum of recovery and significant improvement rate, after treatment with CHM versus conventional medications were compared. Their results indicated that the overall effects favored CHM, which was consistent with our conclusions. However, Gu et al. noted a high heterogeneity for this outcome assessment, and subgroup analysis revealed that corticosteroid creams used as control interventions might be one source of heterogeneity. They also showed no difference between the CHM and control groups in the outcome of the overall severity score. SCORAD and EASI scoring were only analyzed by two studies, which made quantitative data analysis impossible. Moreover, these studies showed fewer AEs in the CHM groups compared to the control groups, which was also contrary to our findings. Their study did not address itching severity, skin sebum, recurrence, or quality of life in AE patients.

The present study has some limitations. First, the sample size of this study was relatively small, which inevitably bias the reliability of results. However, meta-analysis can accumulate sample sizes to achieve higher statistical power than individual studies, thereby increasing the reliability of the pooled results. Second, CHM formulation, theory, and delivery methods greatly differed among the 17 RCTs, therefore inevitably introduce heterogeneity to affect the robustness of pooled results. Third, the patients were highly heterogeneous, as children and adults with AD, AE, and eczema participated in the study. More importantly, sensitivity analysis also showed significant changes in pooled results. Therefore, our findings should also be further validated in future studies. Fourth, treatment outcomes were evaluated by a variety of criteria, and there was a lack of reliable diagnostic criteria among the included studies, especially for patients of a wide range of ages. Furthermore, all eligible studies reported limited data on objective indicators, making a data synthesis impossible. Therefore, we suggest that future studies design objective indicators to further evaluate the effect of CHM on AD.

Conclusions

CHM combined with modern medicine for AD showed better effectiveness than modern medicine alone or placebo in the overall recovery rate and recurrence rate. Our findings may contribute to the management of dermatitis and eczema diseases. However, more high-quality studies are required to substantiate the therapeutic role of CHM in improving disease/symptoms severity as sensitivity analysis significantly changed the pooled results. Moreover, more high-quality RCTs with a large sample size are warranted to investigate the impact of CHM on QoL.

Ethical approval

This article is a meta-analysis. The data come from published articles and does not require ethical approval.

Author contributions

(I) Conception and design: Jinjing Jia; (II) Administrative support: Dacan Chen; (III) Provision of study materials or patients: Junfeng Liu, Xiumei Mo; (IV) Collection and assembly of data: Jinjing Jia; (V) Data analysis and interpretation: Jinjing Jia, Sherman X. Gu; (VI) Manuscript writing: (all authors); (VII) Final approval of manuscript: (all authors).

Acknowledgment

We thank the Young Talent Support Project of Guangzhou Association for Science and Technology, and Young Elite Scientists Sponsorship Program by CAST (YESS20220609) for their support.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All data generated or analyzed during this study are included in this published article.

Additional information

Funding

This work was funded by the National Natural Science Foundation of China (82274521), Basic and Applied Basic Research Project of Guangzhou (2023A04J0449) and Research Fund for Bajian Talents of Guangdong Provincial Hospital of Chinese Medicine (BJ2022KY06).